Passerini reaction

A concerted mechanism, seen in S_N2 and Diels−Alder reactions, is theorized to occur when the Passerini reagents are present at high concentration in aprotic solvents.[10]

This mechanism involves a trimolecular reaction between the isocyanide, carboxylic acid, and carbonyl in a sequence of nucleophilic additions. The reaction proceeds first through an imidate intermediate and then undergoes Mumm rearrangement to afford the Passerini product.[13][14]

As the Mumm rearrangement requires a second carboxylic acid molecule, this mechanism classifies the Passerini reaction as an organocatalytic reaction.[14][15]

In polar solvents, such as methanol or water, the carbonyl is protonated before nucleophilic addition of the isocyanide, affording a nitrilium ion intermediate. This is followed by the addition of a carboxylate, acyl group transfer and proton transfer respectively to give the desired Passerini product.[11][7]

The original Passerini reaction produces acyclic depsipeptides which are labile in physiological conditions. To increase product stability for medicinal use, post-Passerini cyclization reactions have been used to afford heterocycles such as β-lactams, butenolides, and isocoumarins.[16] To enable these cyclizations, reagents are pre-functionalized with reactive groups (ex. halogens, azides, etc.) and used in tandem with other reactions (ex. Passerini-Knoevenagel, Passerini-Dieckmann) to afford heterocyclic products.[16] Compounds like three membered oxirane and aziridine derivatives, four-membered b-lactams, and five-membered tetrasubstituted 4,5-dihydropyrazoles have been produced through this reaction.[12]

This reaction has also been used for polymerization, monomer formation, and post-polymerization modification.[20][21][22][17][23] The Passerini reaction has also been used to form sequence-defined polymers.[24] Bifunctional substrates can be used to undergo post-polymerization modification or serve as precursors for polymerization.[10][11][8] As this reaction has high functional group tolerance, the polymers created using this reaction are widely diverse with tuneable properties.[20] Macromolecules that have been produced with this reaction include macroamides, macrocyclic depsipeptides, three-component dendrimers and three-armed star branched mesogen core molecules.[12]

Passerini reaction has been employed for the formation of structures like α-amino acids, α-hydroxy-β-amino acids, α-ketoamides, β-ketoamides, α-hydroxyketones and α-aminoxyamides.[12] The Passerini reaction has synthesized α-Acyloxy carboxamides that have demonstrated activity as anti-cancer medications along with functionalized [C60]-fullerenes used in medicinal and plant chemistry.[12][25] This reaction has also been used as a synthetic step in the total synthesis of commercially available pharmaceuticals such as telaprevir (VX-950), an antiviral sold by Vertex Pharmaceuticals and Johnson & Johnson.[12]